Faecal microflora and beta-glucuronidase expression are altered in an irinotecan-induced diarrhea model in rats.
OBJECTIVE
Chemotherapy-induced diarrhea (CID) is a well recognized side effect of cancer treatment. However, the pathophysiology behind this debilitating side effect remains unclear. Irinotecan causes cholinergic and delayed onset diarrhea in patients, in which beta-glucuronidase produced by gut bacteria is thought to be involved.


RESULTS
Diarrhea occurred, as expected, following irinotecan treatment. beta-glucuronidase expression increased in the jejunum and colon. Faecal flora changed quantitatively after treatment also, with increases in E. coli, Staphylococcus spp. and Clostridium spp. (all beta-glucuronidase producing) and decreases in Lactobacillus spp., Bifidobacterium spp. (both beneficial bacteria), and Bacteroides spp. (beta-glucuronidase producing, major component of intestinal flora).


METHODS
Rats were treated with 200 mg/kg irinotecan and killed at various time points up to 72 h. Rats were monitored for diarrhea. Sections were stained for beta-glucuronidase expression, and faecal DNA was analysed using real time PCR.


CONCLUSIONS
Irinotecan-induced diarrhea may be caused by an increase in beta-glucuronidase producing bacteria. However, the increase in bacteria may also be caused by irinotecan, further exaggerating the toxicity of the drug and emphasising the need for these specific bacteria to be therapeutically targeted for successful treatment regimens to be accomplished.
Stringer
Andrea M
AM
Department of Medical Oncology, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia. andrea.stringer@imvs.sa.gov.au
Gibson
Rachel J
RJ
Logan
Richard M
RM
Bowen
Joanne M
JM
Yeoh
Ann S J
AS
Keefe
Dorothy M K
DM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D001419:Bacteria / Q000201:enzymology; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D003967:Diarrhea / Q000139:chemically induced* / Q000201:enzymology; D004926:Escherichia coli / Q000187:drug effects / Q000302:isolation & purification; D005243:Feces / Q000382:microbiology*; D041981:Gastrointestinal Tract / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007422:Intestines / Q000201:enzymology / Q000382:microbiology; D000077146:Irinotecan; D007583:Jejunum / Q000201:enzymology; D007778:Lactobacillus / Q000187:drug effects / Q000302:isolation & purification; D051381:Rats; D013210:Staphylococcus / Q000187:drug effects / Q000302:isolation & purification
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D005966:Glucuronidase; D002166:Camptothecin